TNR: Gout Journal Club Save

Hello everyone. Welcome to Tuesday night rheumatology with RheumNow. Tonight in our first TNR of this month, which is gout month, we're going to do a journal club. Let's just start by everyone introducing themselves and where they're from. I'm Jack Cush in Dallas, Texas.

Dr. Good evening everyone. This is Jay Wei from Xiang Ya Hospital, Central South University, China, and thank you for inviting me to join this webinar. It's a pleasure to be here and I look forward to today's presentation and discussion.

Yes, Dr. Wen. Hello everyone. This is Xin Wen from Xiang Ya Hospital, Central South University. Thank you for inviting me and I'm looking forward to having a good time with all of us.

Excellent. Thank you, Professor Abhishek. Oh, hi. I'm Abhishek. I'm a rheumatologist and a professor of rheumatology at the University of Nottingham and Nottingham University Hospitals NHS Trust and thank you for selecting this article for discussion today.

And Dr. Dalbowski. Hi everyone. I'm Ugrowski. I'm a second-year rheumatology fellow at NYU and I'm excited to be here.

Okay. So in this program we want to first thank the sponsor of our gout month here in July. That would be Sobi Pharmaceuticals, which is supporting the education we're delivering this month. Today we're going to go over two articles that I have listed for you there. We have the authors here and fellows to present the articles. We're going to also review survey results that we sent out just yesterday and we got a lot of survey answers that will help the discussion when we get into the articles. We're going to hear from you the audience at any time if you have a question. Use your Q&A box to write in your question. Not the chat box, but the Q&A box.

Okay. So you've met everyone. We're going to have the fellows present our articles, with Igor from NYU presenting the treat-to-target and cardiovascular outcomes article and Dr. Wen from Central South University presenting the same treat-to-target but renal outcomes.

Okay. So I want to remind the audience that ahead of these TNRs we do surveys. We send a one-time survey question and 277 of you answered that yesterday. Half from the United States. That was 86% rheumatologists, 2% fellows, and 5% APPs. And we asked a total of eight questions. We're going to review about six of them here in this program. And again, we're going to discuss these two articles. Interestingly, both of them were from JAMA Internal Medicine. Professor Abhishek's article appeared in March of this year and Dr. Wei's article appeared in 2025, also in JAMA Internal Medicine.

But let's begin, since the whole point of these journal articles was the impact of treat-to-target. I wanted to ask you the audience about treat-to-target, and the first question was — again, 277 people responding, most 86% rheumatologists — how often do you achieve a serum uric acid of less than six in your gout patients? 55% of you said greater than 75% of the time, 29% said 60% of the time, only 13% said 40% of the time. And the shocking thing here is the research. I'm sure all of you are doing all this, but when we look at actual data from rheumatologists it's only about 40% of you are achieving target. Now that same number, or a little bit less, 30 to 40%, is what happens in primary care, and you would think the rheumatologist would be better, but the research is not all that great.

Dr. Abhishek, why do you think that is? Yeah, I mean it's — I think you gave some UK, some US data, and in the UK we have the same situation. We did a national audit and 30 to 40% of primary care physicians and hospital rheumatologists achieve treatment target with urate-lowering therapy, and I think the main reason for that in primary care is the fact that in primary care in the UK doctors don't give follow-up appointments to patients to properly escalate therapy and engage with them. So I think there's a big problem there, and in secondary care we sometimes get really blindsided by, you know, rheumatoid arthritis and vasculitis and lupus and just say, oh well it's gout, and sort of ignore it a little bit. So there's a bit of physician inertia I think in hospital practice. But most gout is managed in primary care and I think the bigger problem there is that there is no structured treat-to-target with blood tests to check urate levels and escalate doses. I think that's the main reason.

And you're absolutely right. One of the featured gems that we put on the website yesterday was that in the United States there are 12.1 million people with gout but only 1.3%, certainly no more than 3%, of them are seen by rheumatologists. So that's a bit of a problem.

In China, Dr. Wei, do you have the same problem of not achieving treat-to-target as much as you're supposed to? Yes, we have. And the problem is patients in China — we do not have the primary care center. So the patient only has symptoms to go to the
hospital to have the prescription and during their daily time if they do not have the symptom they do not have the gout flare. They always do not take the medicine. So I think the the the the the second test was severe in China. XC yeah situation.

So the second question lends support to maybe what the problem is. I gave a scenario. You're managing a patient with a uric acid of 6.3. You're not at target but you're close. Uh on 300 milligrams of allopurinol. Do you escalate the dose? 53% said yes. 31% said depends. And 15% said no. You could see that strict adherence to treat to target is not being practiced by almost half of of the of the respondents in this and again half are from the US and half are outside the US. So again I maybe the point of this is that if you listen to these articles are you more motivated to achieve target um and we're going to get into those articles um next.

So let me see what we have here. All right. So, let's begin with the professor Abhishek's article from March of this year. Uh, Igor, why don't you present this uh this paper?

Sounds great. Um, so today I'll be presenting a study published by Cipolletta et al. um in JAMA in 2026 entitled treat to target urate lowering therapy uh urate lowering treatment and cardiovascular outcomes in patients with gout. So we know gout is associated with approximately a two-fold increased cardiovascular risk. This study evaluated whether a treat to target strategy in gout um uh within uh 12 months of initiating urate lowering therapy is associated with a lower five-year risk of major adverse cardiovascular events. Uh it used the target trial emulation design. Um and eligible adults were residing in England registered in a general practice that contributed data to the um Clinical Practice Research Datalink CPRD between 2007 and 2021 uh with linkage to hospitalization and mortality records. Um they were required to be diagnosed with gout, uh have received their first urate lowering prescription on or after the first diagnosis date and have a latest pre-treatment serum urate higher than six. Um notably this also included CKD patients. 99% of patients were on allopurinol. 86% were white.

Uh the intervention was achieving a serum urate less than six. So patients were assigned to the treat-to-target urate lowering therapy arm if their urate level was less than six within 12 months of the first prescription and assigned to the non-treat-to-target arm if all serum urate levels were uh six or higher in the 12 months of first urate lowering prescription or if it wasn't measured. Uh the primary outcome uh was a first major adverse cardiovascular event within five years following the first prescription. Uh and uh positive controls included uh the number of gout flares you would expect to to target urate lowering therapy to reduce the number of gout flares and negative control outcomes were chosen to assess for presence of unmeasured confounding including acute bronchitis, cataracts and appendicitis uh as there was thought to be no plausible mechanism by which they can be caused by achieving or not achieving the target and uh addressed a range of mild, severe and chronic illness.

Um so 109,554 patients met eligibility criteria. The mean age was 63 years. 78% were male. Um the mean standard disease duration uh was 2.5 years. 27% of patients were included in the treat to target group. Um and um uh as you can see so after applying inverse uh probability weighting to emulate the target trial the investigators estimated a 5-year uh major adverse cardiovascular event free survival in the two groups um and MACE free survival was 89.4% in the treat-to-target group. Uh 88.3% in the not treat-to-target group which corresponds to an absolute risk difference of approximately 1 percentage point. Our number needed to treat of 91. The weighted hazard ratio was 0.91 with a 95% confidence interval of 0.89 to 0.92. Um cardiovascular risk category also showed clear effect modification with meaningful absolute and relative risk reductions in patients with high and very high baseline cardiovascular risks. Uh the positive control outcome gout flares behaved as expected with a reduction in flares among those achieving target. The negative controls showed no association uh supporting internal validity and also uh the investigators evaluated whether achieving a stricter urate target uh below 5 milligrams was associated with different cardiovascular outcomes. Um and they found that in that analysis um uh there was a uh a dose response relationship uh um with a hazard ratio of 0.77 absolute difference of 2.6.

The main conclusion was that achieving serum urate less than six within 12 months was indeed associated with a lower five-year risk of MACE. Um and in the next slide um I'm just going to go over uh some of the baseline characteristics. The mean age you can see was 62.9 years. About 78% were male. Um in terms of alcohol only 18% reported greater than 21 units per week. In terms of smoking only 10.2% reported being current
smokers. Uh 45% of patients were obese. Uh notably 23% were CKD stage three to four and 3.2% were on dialysis and it's notable that this population was included in the study. 55% had hypertension and only about 30% were in the low or moderate European Society of Cardiology cardiovascular risk category. Uh the takeaway here for me being that this table shows a predominantly male older high-risk population with substantial cardiometabolic disease.

Um now now um I think Dr. Abhishek is going to comment a little bit more on this. Um but in the meantime I can talk about the primary outcomes. Uh so in figure A you can see the Kaplan-Meier curve shows modest separation beginning after about a year. Um and the survival curves separate gradually over time, which makes sense if you're reducing a chronic inflammatory burden. Among patients with gout, newly prescribed urate lowering therapy, those achieving serum urate less than six within 12 months had a substantially lower risk of MACE.

Um the crude 5-year event-free survival rate in the treat-to-target uh urate lowering therapy and non-treat-to-target urate lowering therapy arms uh was 89.9% and 87.8% respectively with a survival difference of 2.1. Um um and the the five-year weighted event-free survival rates in the two populations were 89.4% and 88.3% respectively with a survival difference of 1.0% uh 95% confidence interval of .5 to 1.6.

Um in terms of secondary outcomes there was a hazard ratio of .88 with MI, .86 with stroke. Uh positive control outcome gout flares behaved as expected with a reduction in flares and the weighted controls again showed no association supporting internal validity.

Um Dr. Abhishek do you have anything else you'd like to add about this? Yeah, thanks. Thanks, Agore. It's an excellent presentation. Um, and as colleagues can see, there's no association with negative control outcomes. And I just wanted to comment on a couple of things. So, um, this was a sort of a the primary analysis, but we looked at um hospitalization or death due to MACE, which is more of a hard end point, and again there was um there was an effect on that. Um we looked at um people at high or very high level of cardiovascular risk and in that population there was an even larger effect size.

Um so I think they're the two points that increase confidence in these findings apart from the absence of residual confounding and the thing to remember is this is not a clinical trial. This is uh a new user cohort study done using an emulated target trial framework. We try and minimize any confounding that we can and obviously the absence of residual confounding gives confidence that you know what we have found is a true effect. Really small 1 percentage point improvement in MACE over 5 years but you know it's 1% of our disease is still a lot.

Um the other thing I wanted to draw your attention to is — can I interrupt a second? I just want to use the line that you used in your paper. 1% doesn't seem like a lot, but in 2020 55 million people have gout. And by 2050, what was the number? 95, 96 million. I mean 1% of that is a gigantic difference. And that's why this is so impactful. I'm sorry to interrupt. Go ahead. That's fine. I was I was being um — Yeah, that's absolutely spot on. Um thanks for for coming in.

I can just talk to you about the graph that is shown here on the top, graph A. And as you can appreciate the the T2T arm and the non-T2T arm, the the events are comparable for 18 months or so. And then the T2T arm begins to sort of show better survival. And this you know may point that that this sort of the the mechanism of improved survival is sort of uh absence of flares or or freedom from recurrent flares because in the trials that we did in Nottingham we found that if you give somebody T2T for one year it doesn't improve their flare rate. The flare rate only improves in the second year of treatment with T2T. And then we did some follow-on work which showed that if you continue with T2T then you get almost freedom from flares thereafter.

So it's possible that the um the improvement in MACE-free survival in T2T is driven by fewer flares. Obviously, we can't prove that um because in CPRD only those flares where there's a consultation um and a diagnosis and a prescription can be called a gout flare validly. You know not every gout patient consults the GP for every gout flare because they know how to manage it, self-manage it. So not everything is captured.

Um I think I want to interrupt and say that the um the old people remember that when uh especially when febuxostat was being developed and being compared to allopurinol if you looked at flare rates with the initiation of ULT it was horrible in the first 6 to 12 months because in lowering uric acid you're mobilizing a lot of urate and you're causing lots of flares which is why they need to be on prophylaxis. Um and that's and so that goes along with your point that the real separation, real
benefit is after that first year. Yeah. And and UK primary care, you know, colchicine prescription if it happens with T2T LDS for a couple of months. We did a separate — we did a different paper on that where we found that the average prescription was like 40 days or so. So it's not not long-term prescription by any means as ACR recommends or even the BSR recommends. Right.

Um yeah, they're the only points to make really. Thanks. Thanks, a excellent presentation. Over to you again.

I have a question since uh both um professors Abhishek and Wei um a present or did a great T2T study uh with different outcomes, put it in JAMA Internal Medicine, but they also — they both use a target trial emulation design. Um professor Abhishek, why don't you take a stab at that first as to why you chose it, chose to do that, and and isn't there a limitation of that because you're going — you're using the CPRD database which is a lot of mostly primary care not specialty care and whatever, but um why did you choose to do that? What's the limitations of the target trial emulation design?

So I mean good question and thanks for asking. So target trial emulation is supposed to be used or recommended or advised to be used when a — when a sort of traditional randomized control trial is not feasible. So this is a situation where uh you can't really withhold patients from getting treated — target urate lowering therapy if they've got active gout with flares etc. So it'll be unethical to randomize patients with gout who've got symptomatic gout flares etc to not receive urate lowering therapy. So in these situations um where actual large pragmatic RCTs are not possible we could use existing data to do um a target trial emulation.

Now target trial emulation is not a randomized control trial and does not — does not involve randomization but it does involve complicated methodologies to balance or minimize uh any any bias from um um from cloning. So you sort of essentially clone the participants into into two arms and so that there is no difference in the two arms at baseline. Then you sort of um censor the follow-up time when they deviate from their allocation and you weight this — this follow-up time according to the probability of of survival uh to to the allocated time point. So by cloning, weighting, and censoring we hope to minimize residual confounding and again we can measure that by looking at negative control outcomes. But you know the the limitation is that it is not a randomized control trial.

And one of the problems of looking at external databases like CPRD is is um we sort of look at 20, 25 years worth of worth of data. Um and and and you know some of the temporal trends in cardiovascular survival etc might have an impact on the finding. We did look at more recent patients as well in the sub-analysis where we found similar results. So we're happy that that doesn't have a big impact. But yeah, so both these trials um have limitations but again the strength is the numbers um and the the cloning which to represent the randomized groups.

Um Iqra, you want to just uh wrap up with these um strengths, weaknesses and conclusions.

Yes certainly. Um so uh some of the — we already discussed that you know the modest reduction but with large population implications. Um some of the notable strengths are that you have linked primary care hospitalization and mortality records um for all outcomes. You saw a dose response which is of of interest and the positive and negative controls were uh validated um validated the results. Some of the limitations are uh we may have would included patients with a history of MACE. Uh so there's some risk of confounding and some patients may have been incorrectly diagnosed with gout um or have been — or patients who were on treat to target urate lowering therapy might have had um you know better patient management.

But the conclusion stands that achieving serum urate levels lower than six within 12 months did uh was indeed associated with statistically significant uh lower 5-year risk of MACE. Um and just to you know again reiterate that this is not a a randomized control trial. Um so the the causality here remains unproven but it is a powerful illustration in favor of this uh concept that treat to target may have — may confer other benefits than simply reducing flares including lowering cardiovascular risk.

So um I have um some survey questions I want to give to the group and professor Abhishek, but do any of the other uh panelists have questions for uh on this paper before we move on?

Okay so one of the um survey questions that we did was what percentage of gout patients have cardiovascular disease? How important is this? Is — most of us that manage gout we know some of them have history of MI, they have hypertension, there's obesity, metabolic syndrome, it's not surprising, but you know what is the number and you know this is — you're kind of — all the all of you are all over the map saying it ranged anywhere from uh 10% — 1 and 13% of you said that um uh 20% was
chosen by 30% of you and 30% was chosen by about a third as well. So it is, I must say, a messy area, and when you get a patient who's newly diagnosed or looked at baseline, it's at least 20% and often as high as 30, maybe even as high as 47% in different cohort analyses.

My point in asking this question was that this is a common issue and hence this goal is an important goal. Um, what do you think, Professor Abhishek? Yeah. No, I mean, you make an absolutely valid point, and I mean, if I remember correctly, in most primary care-based gout datasets, large datasets, about 40% of people have got hypertension with gout, and again another 10–15% hyperlipidemia, obesity is very common. Um, if you combine ischemic heart disease, heart failure, CKD as a more serious end, that's about 20% odd people between them. So it is fairly common to have cardiovascular disease or strong risk factors for cardiovascular disease at diagnosis.

And again there was work done by Jing Fen, who was in Nottingham about 10–12 years ago, and they showed that not only is comorbidity common at diagnosis, it gets even more prevalent as time goes by in people with gout, and the increase — the relative increase — is more than in the general population for age-sex matched controls. That's so true. So it's a serious problem. Yeah.

And that's why this treat-to-target outcome is really important. Um, which I asked the audience: which of the following gout drugs lower cardiovascular risk? And I put stars next to the right answers. 24% of you said allopurinol, but 61% said that it's colchicine, probably thinking that colchicine has this new cardiovascular indication across the board. But the data in my opinion for cardiovascular risk reduction is far stronger for allopurinol than it is for colchicine, but it exists for both. Um, but there aren't great studies for febuxostat or other urate-lowering therapies. Is that true, Dr. Abhishek? Yeah, I mean, I definitely agree with you and agree with the respondents. So urate-lowering therapy long-term and colchicine — they both have got signal, and I think this is also an important point: that when we are starting people with gout on urate-lowering therapy using a treat-to-target approach, then we should also consider prescribing colchicine gout flare prophylaxis for say 6 months or longer, when flares are actually common. Um, but yeah, I agree, and I think these are absolutely spot-on correct answers.

This last question I want you to help clarify, because we said an EULAR graph showed those lines being close but diverging with a 1% difference over time. Um, I asked the question: if you achieve uric acid less than six, how much does that lower cardiovascular risk by? And they were a third, a third, a third — either 10%, 20%, or 30%. That's not 1%. Do you want to explain this, Dr. Abhishek? Yeah, I mean, it's possible people are thinking of relative risk reduction, where we've got about a 10% relative risk reduction, but the absolute risk reduction is 1%. And if I can put this in context: in gout patients with a 5-year follow-up, the absolute risk of CV or MACE is 13%. So that's the sort of overall risk, and it reduces from 13% to sort of 12% in the whole gout population. And in those at high or very high risk it reduces by a little bit more — so 2 percentage points. So the absolute reduction is not huge, but the relative reduction is, as it says, about 10%. So again, cardiovascular mortality in gout is mostly driven by heart and cardiovascular events, but kidneys are equally important.

That's why we're going to discuss the Wang-Edall article from Dr. Wei's group that appeared in 2024. I asked the audience the same questions. Um, what percentage of gout patients have CKD at stage three when you see them? And the most common answer, by 42%, was 25%. And that's probably close to the right answer. Um, some thought it was only 15%, 50%, and 24%, but the right answer from the literature I could find is about 24% will have CKD at stage three — it's up to 60 cc's per minute. If you look at stage two, it's much higher — it's like 70% will have stage two CKD at presentation.

And then I want to get feedback from our panelists as to what is the goal in treating — and I didn't know the answer when I made up this question — but what is the goal in a gout patient who has CKD, let's say stage three or whatever? What is your goal? And you were all over the map, and I don't know there is a right answer, but I'm going to ask everybody on this panel: what, if you had to choose one — and that's the problem with these multiple choice questions, you only get one choice — the most of you chose a uric acid of less than six. And we're going to see the data on that. Um, that was 42%. Next was a uric acid of less than five, that was 21%. Preserving renal function at 18%, and 16% avoiding gout attacks. Um, Dr. Wei, what do you think is the right answer? What is the goal, besides all of these of course? Yeah, from my
opinion I will choose less than six because first of all this is a guideline recommendation and secondly from our data we actually — I'm not sure the lower the better because we don't have enough data to do the analysis because in the database, in the real world, the actual patients received the serum urate level less than five is quite low. So we cannot do the analysis to check if the lower is better. So from now we only have the data for less than six. So I will choose less than six.

Dr. Wang, what would be your choice on this question? Uh, maybe also less than six milligrams per deciliter. And I think we're going to see the value of that when we look at the paper. So I think those two are kind of biased a little bit, but um, Igor, what's your goal here? Um, I would say the guidelines recommend less than six, but intuition tells me that overall the lower the better. Uh, but I defer to our experts here. And Professor Abhishek, what do you think? Yeah, I'm happy with what others say. Less than six would be my answer as well, again all being true to treat to target. Um, Dr. Wang, go ahead and present this paper.

Okay, good evening everyone. Today I will briefly present this study published in JAMA Internal Medicine. The clinical question was: in patients with gout and stage three chronic kidney disease, or CKD, is achieving the serum urate targets with urate-lowering therapy, or ULT, associated with worse kidney outcomes? Treat to target with ULT is central to gout care. Both the ACR and EULAR recommend lowering serum urate to below 6 mg per deciliter. However, CKD affects approximately one-third of patients with gout. Clinicians may hesitate to optimize ULT when kidney function is impaired because they worry that intensive urate lowering could worsen CKD progression. Previous trials didn't fully answer this question as most didn't focus specifically on patients with gout or evaluate kidney outcomes according to target achievement. Therefore, this study evaluated the association between achieving the serum urate targets with ULT and CKD progression in patients with gout and stage three CKD.

Let me now turn to the study design and main findings. Using the Auvia medical research database from 2000 to 2023, the investigators included eligible adults aged 40 to 89 years with gout and stage three CKD. They compared two ULT strategies: achieving a serum urate level below 6 mg per deciliter within one year of ULT initiation versus not achieving this target. The investigators emulated a target trial using a cloning, censoring, and weighting approach. At initiation, each patient was cloned into two copies with one assigned to each strategy. During the one-year grace period, the target-achieved copy was censored if the target was not reached by one year. Conversely, the target-not-achieved copy was censored once the target was achieved. When severe or end-stage kidney disease, death, or loss to follow-up occurred before target achievement, both copies remained adherent to their assigned strategies. After target achievement, subsequent events contributed only to the target-achieved arm. The probability of remaining adherent was estimated using logistic regression with baseline and time-varying covariates. Inverse probability weights were then applied to reduce selection bias from artificial censoring. Patients were followed for up to five years and the primary outcome was severe or end-stage kidney disease.

As shown in the curves, risk was consistently lower in the target-achieved group. Next slide. The third slide — and again, what's the difference between panel A and panel B? Panel A includes people on hemodialysis, transplant — is that right? And the other one is just end-stage kidney disease? On panel B, the population is the same but the outcome is different. In panel A the outcome was severe or end-stage kidney disease, and in panel B the outcome was end-stage kidney disease alone. Okay.

The study included 14,792 adults with gout and stage three CKD. Their mean age was 73.1 years and 62.3% were men. At five years, the risk of severe or end-stage kidney disease was 10.32% in the target-achieved arm compared with 12.73% in the target-not-achieved arm. The adjusted risk difference was minus 2.41 percentage points with a 95% confidence interval from minus 4.61 to minus 0.21. The adjusted hazard ratio was 0.69 with a 95% confidence interval from 0.48 to 0.98.

A major strength was the attempt to reduce selection bias among ULT initiators and confounding by indication because all participants received ULT. However, residual confounding cannot be ruled out. Patients who achieved the target may also have received better healthcare overall. Achieving the serum urate target with ULT was well tolerated in patients with gout. This finding supports optimizing ULT to achieve the serum urate target in patients with gout and impaired kidney
function. That's all. Thank you. Okay, that was great. Um, Dr. Way, do you — let's first begin with your views on using the target emulation trial design here, doing a trial that couldn't easily be done, but do you have any hesitations presenting that kind of data?

Yeah. So we do this analysis based on our previous — based on previous trials, because previous trials demonstrate that in recent trials there's no real benefit when treating patients with CKD and lowering their serum urate. But our concern is if the patient had gout we should be treated, and they have both gout and CKD — should we treat them to the target? So this is how we start, and we do the trial emulation, because to do such a trial is invisible, right — we cannot control the patient not to reach the target. So we do the trial emulation.

So the target trial emulation — the key is to solve the problem of the immortal time bias. What is immortal time bias? Patients have to be treated; they must survive long enough to achieve the serum urate level. So this time period is called the survival time, during which the outcome cannot occur if patients are eventually classified into the treatment group. So this artificially favors the treatment group. So our design is to assign the treatment at the start of the follow-up. So we minimize the immortal time bias by aligning treatment assignment with the start of the follow-up. We account for the time-varying confounding, minimize the selection bias, and strengthen the causal inference from the real-world data.

So as a conclusion from our study, we found that the group who achieved their target level did not show higher incidence of the progression of CKD. So our data — we do not support that treating to the target serum level is renal protective. We do not say that we treat the chronic kidney disease. We only say that the treat-to-target strategy is safe and does not accelerate the safety progression. So the goal is to tell the rheumatologists we could treat the gout patient with CKD to the target and it's renal safe.

So that's — I think it's very interesting that both these trials have incidence rates on primary outcomes that are kind of around 10%, with about a small difference between them: 1% with the cardiovascular trial, 2.4% here. But these are significant, and significant given the deadly, disastrous outcomes that occur when you don't control renal disease and don't check cardiovascular disease. So these are, I think, tremendously important outcomes.

You know, when I ask the rheumatologist if a gout patient has CKD four or five — they're advanced — what's the top dose of allopurinol that you would use? And look at this — the audience is all over the map. The top dose — I don't know where this comes from — is 100 milligrams in 45% of people. That's totally wrong. That's your starting dose. That's not your top dose. That's your starting dose per guidelines. And then 300, 19%; 400, 16%. And then the right answer — I'm sorry, 300 was — what? I got confused here. Eight. Right answer is 20% here at 800. You can go as high as you want with renal disease. You just have to monitor the kidney.

Renal doctors — one of our audience docs says nephrologists keep saying increasing the dose of allopurinol worsens renal failure. How concerned should we be, and should we use febuxostat instead? No. I mean, you can, but allopurinol I think has over and over and over again been shown to not be a truly nephrotoxic drug. You have to monitor renal function, but you can use up to 800 milligrams at any creatinine level as long as you're monitoring renal function.

Does anyone have an alternate opinion here about this?

I agree that we should monitor the renal function and also the serum urate level. And the target — the goal is to treat to the target, no matter what dose you use. The goal is to reach the target. So I think the doctor may be too conscious about the dose. The goal is the serum urate level target. So I agree with Jack.

Yeah. Um, Luis Torres asked, "Should we still adhere to the protocols of Lisa Stamp from New Zealand with regard to dosing allopurinol in CKD patients?" Lisa's going to be on one of these panels I think in two weeks and we can ask her, but I think yes. And she escalates and has a formula for escalation based on uric acid levels and renal function.

So, Katherine Garcia asks, "How frequently should we be monitoring the estimated GFR and creatinine in these patients?" I mean, depends — no problem, not that much, 3 to 6 months. If there's a problem, more frequently, or if you're starting out in the face of, you know, whatever. But um, Professor Abbashek,
how do you recommend monitoring creatinine and eGFR in these people? I mean, I think that depends on what the renal doctors want to do. Um, I mean, as my understanding is allopurinol or even febuxostat are not nephrotoxic. So, you know, having gout doesn't mean you need to check urate creatinine more regularly. So for most of these patients I believe nephrologists do three monthly blood tests in UK to keep an eye on the kidney function.

I wanted to make another point about using allopurinol in CKD. I think we can escalate the dose to whatever is needed to control urate level less than six. The important thing is to start at a really low dose like 50 or 100 milligrams daily to reduce the risk of allopurinol-induced severe cutaneous toxic epidermal necrolysis or DRESS syndrome. So start at 50 or 100 milligrams a day and then escalate monthly to get to target and that's what Lisa and Nicholas's paper show safety of.

Um yeah, John Tesser in Arizona brings up the question, is there safety data for 800? There is because the trials were done with up to 800 milligrams. But there's a group of gout advisers that have been setting up a lot of the curriculum for these webinars and what we're rolling out this month. And we discussed two weeks ago that there isn't a lot of guidance about what to do when you're, you know, at an eGFR of greater than 60, because the uloric data, the febuxostat data, they have data on its safety up to an eGFR of 60 not beyond that, so there's just, you know, clinical experience and whatnot. But I think John's point is that maybe the hesitancy is that people haven't been shown the data showing that it's in fact real, but there are a lot of case series that show you can certainly go up higher.

The truth is that if you look at the average dose of allopurinol in gout patients in primary care it is 300 milligrams. And that's the median — the median dose of allopurinol in rheumatologists is 300 milligrams. The number of people that go to 600 and 800 is still very very low. And again I think that to me I find that worrisome and we're kind of wimping out on treat to target. I mean you should be pushing the dose to get to the target or using a drug that's going to get you to the target.

You know, we have one person asked a question about is there evidence for either cardiovascular or renal protection in using ULT in asymptomatic hyperuricemia patients. Now that's not what was done in your trials, right? Those had to be patients with gout. But is there any on asymptomatic? Yeah. I mean for cardiovascular disease there are a couple of trials. There is a really large trial led by Isla Mackenzie from Scotland which showed that if you treat asymptomatic hyperuricemia patients with urate lowering therapy you have absolutely got no effect on cardiovascular outcomes. That's a proper RCT, a large RCT published in Lancet by Isla Mackenzie, so we should definitely not be treating asymptomatic hyperuricemia with urate lowering drugs to prevent cardiovascular disease. And I think that's been also said for use of oxypurinol in heart failure patients who have hyperuricemia — similar results are seen there.

Dr. Wei, I'm sorry to interrupt you. Yeah. So there's another paper just published this year, another group in China. They do a similar analysis but they restrict the population to asymptomatic hyperuricemia and CKD and they similarly do not find a significant association between reaching the target and CKD progression. So I would say that the benefit may not be so significant in the hyperuricemia population.

I like that point. We have another question. What is most disappointing about the care of gout? I'm going to write about this because I have a survey that asked this question along with the major advances in gout that goes back to Jim Fries from Stanford, I think 1986, and then I did a repeat survey with 500 rheumatologists in I think 2014 and now I'm asking the question again. And what is most disappointing with the care of gout patients? Your number one answer, 46%, was patient non-compliance. Number two answer at 19% was treatment by non-rheumatologists. You know, this is kind of at the base of treat-to-target failures, right? It's partly patients. It's partly those who aren't pushing on the numbers. And you as rheumatologists have to take some responsibility for that as well.

But what do you think of these answers? G, do you think that this is surprising to you? No, not surprised. First, the patient non-compliance is very obvious in previous research, also in our research — less than like 30% of patients adhere with their therapy and reach the target. So I think this is the number one disappointing about care of gout patients, and number two, treatment by non-rheumatologists. I don't think this is a situation in China because I think people always go to the rheumatologist to treat gout. So I don't think the second reason is
not the situation in China. So that's my opinion. Yeah. Yeah. But the numbers, there aren't enough rheumatologists in China to take care of 40 million people with gout in China. Um so and that's but and that's projecting forward obviously, but still um how do we handle this issue of patient non-compliance? Um I I I'd be interested um in why gout patients are are so non-compliant. Is it because it's an on-off-again disease? Is it is it because of it being men? Um what do you think? Uh uh professor Abhishek. Yeah. So I I mean you you hit you you got sort of the main problem sort of you said that is that it's an on-off disease an intermittent illness. Um but I think the bigger problem is is physicians or health professionals don't explain that it's a chronic illness where the crystals are sat there they flare up. Um and again sort of lack of knowledge of um effective treatment that can prevent flares in the long if taken in the long term with urate lowering therapy. So lack of knowledge of effective therapy, lack of information that how much you modify your diet, you can only reduce your urate level by that much long term. And then there is a huge amount of misinformation online or sort of all sorts of stories about you know different things and potions to prevent flares or treat gout. I think and I think the the the other problem is is that sometimes doctors perceive or clinicians perceive gout as a self-inflicted illness and therefore don't are not as sympathetic towards their patient not as supportive as many times we are for patients with rheumatoid arthritis for example where we think oh it's an autoimmune condition but now we know that most of hyperuricemia is not self-inflicted it is mostly genetic from renal and GI under sort of renal under excretion and GI under excretion. So I think the non-compliance there is patient factors, there's a disease factor, it's intermittent, there's a patient factor, um there's misinformation and then there is a physician lack of sympathy and time um and physician lack of knowledge as well. So I think and you know patients who are they don't care about it until they get a gout attack then they're searching for answers and they're getting treated by everybody in the world who thinks they know how to manage gout and they give them a lot of misinformation um which says oh don't worry I can fix that with this drug or you come to me when you have this problem and as if to say it is an on-again off-again thing.

I want to ask our fellows, how do you manage the non-compliant patient that comes to you in clinic? You know, the patient is supposed to be on therapy, they're not on therapy, they're still having attacks. Um, Igor, what do you do? Well, I would say it's important to have open channels of communication with your patients. Um I think that you know trying to communicate with them via phone uh trying to like reach out and then trying to ask them you know what their understanding is and what their uh you know reasons are for doing XYZ remaining kind of empathetic and open-minded. Um also just to underscore that you know the ACR guidelines do recommend uh treat to target um but the you know the ACP guidelines in the US for primary care physicians uh still um recommend the treat treat uh to symptoms which is basically treating gout flares and not really to a target urate lowering therapy. There's like ongoing research notably like the TRUST trial that uh we're involved in that is trying to kind of assess whether one strategy uh compare the two strategies. Um I would say that what's important though to answer your question again is to maintain open channels of communication and remain empathetic.

Yeah. Uh Dr. W, do you have a a point to add here? Yes. I I have the the the similar idea with Igor. uh there's uh because in China there are so many patients with gout and uh we uh the doctor the number of the doctors is more so we can only uh by communicating with the patients or uh pre prescript prescription uh some ULT medication to the patients uh and uh yeah that's all.

Okay we have a few comments that I want to I want to bring up here. We got a few more minutes. Um, uh, Herb Bar who's done a lot of the trials here says, "Is it fair to say that non-compliance is a product of education, uh, deficiencies, as Professor Abhishek has pointed out?" And the problem with that is we can't rely on rheumatologists to do all the educating since we're only taking care of 1 to 3% of patients. So, where's the rest of the education going to come from? Luckily, there have been major initiatives in the United States to do better patient education. Larry Edwards and others are involved in patient sort of groups. Creaky Joints is involved in educating patients on gout. I think that's important. Uh I like John Tesser's point about maybe you can do better at managing gout by using structured clinics with advanced practice providers um doing most of the work um either face-to-face or by telemedicine um
and why not have what they have in the UK with early access clinics for PMR — why don't you have an early access clinic for gout? If you want to make a bazillion dollars in the United States just do a gout clinic and employ 300 nurse practitioners and make sure everybody can drive up and get their gout care with, you know, no friction.

But John, who has a lot of nurse practitioners and physician assistants, I know that they're probably better at it than we are in my clinic.

Jim Doubt asked: do you think discussing the MACE risk with patients will get their attention and increase compliance? So can you — Dr. Zi and Abhishek — can you use your data to say we have shown, and do you think that motivates patients? I mean, I have used it in a couple of — I only get referred complex gout which is difficult to treat or there's non-compliance issues, and sometimes when patients are not terribly keen I have brought this data and discussed it, and that sort of seems to sway some of them towards urate-lowering therapy. So yeah, I have used it and I think we should use it more widely.

Yeah. Yes, I agree. I think we should use social media to promote our findings in the general population. And our work has been reported in social media. So I think this is one of the ways to educate the population, using our data, our findings. Yeah.

I want to address the last two comments. Luis says, "Is there any studies proving that patient education improves compliance?" I'm not aware of any. I know that there is some work here, but I don't know that data very well. But I think Leica Barbosa's point is the good final point — that rheumatologists, I mean, the key, what we're calling this campaign this month, is "gout is more than flares," which is to say gout is a systemic disease. Gout is a urate deposition tissue damage disease and it has tremendous systemic effects, and in fact using urate-lowering therapy is to say you're using disease-modifying therapy. And to make the point that gout is a systemic disease should be the start of an education program with your patients.

So with that I want to thank our panelists for an excellent discussion on two really important papers in rheumatology. I want to thank our fellows for guiding us through those papers and the audience for their input as well. Next week we're going to have another Tuesday night rheumatology. I'll be hosting Nicole Dalbeth, John Fitzgerald, and Sara Tedeschi, where we're going to talk about uric acid deposition and imaging. Basically, what lies beneath the attack is a lot more — meaning we're getting to the point that gout is a systemic disease and what's the evidence for that. We'll talk about that next week. Thanks very much, folks. Good night.

Thank you. Thank you. Bye. Bye. Bye.